Comparing cryo-EM structures of the vertebrate cardiac muscle thick filament

Area of Science:

• Molecular Biology
• Biophysics
• Structural Biology

Background:

• Muscle contraction relies on myosin motors interacting with actin filaments within thick filaments.
• An atomic-level model of vertebrate striated muscle thick filaments has been a long-standing research goal.

Purpose of the Study:

• To present novel cryo-electron microscopy (cryo-EM) structures of cardiac muscle thick filaments.
• To elucidate the molecular organization of myosin heads, tails, titin, and myosin-binding protein C (MyBP-C) within the thick filament backbone.

Main Methods:

• Three cryo-EM studies utilizing cryo-electron tomography and single particle cryo-EM.
• Analysis of cardiac muscle thick filaments from mouse and human.
• Investigation of filaments treated and untreated with the myosin-stabilizing drug mavacamten.

Main Results:

• Atomic structures reveal myosin heads in interacting-heads motifs (IHMs) on the thick filament surface.
• A complex arrangement of myosin tails, titin, and MyBP-C forms the filament backbone.
• Structures are highly consistent across species and techniques, with minor variations in IHM stability and MyBP-C organization.

Conclusions:

• The reported cryo-EM structures provide unprecedented atomic detail of the vertebrate striated muscle thick filament.
• These findings advance our understanding of the molecular mechanisms underlying muscle contraction.
• Observed differences in IHM stability and MyBP-C organization are attributed to experimental techniques and filament isolation methods.